JPH0859654A - Use of 6-amino-1,4-dihydropyridine compound as remedy for central nervous system and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a selective modulating effect on a potassium channel and useful as a treating agent for the central nervous system.

SOLUTION: This 6-amino-1,4-dihydropyridine is a compound of formula I [A is a 6-10C aryl or pyridyl; D is cyano or nitro; R¹ is H or an alkyl; R², R³ are each H, an alkyl or an acyl; R⁴ is H or forms (CH₂)_n together with R³ and R⁴; (n) is 2-4], e.g. 6-amino-4-(3-chloro-4-trifluoromethylphenyl)-1,4- dihydropyridine-2-methyl-5-nitro-3-carboxylic acid methyl ester. The compound of formula I is obtained by reacting a compound of formula II (R¹≠H) with a compound of formula III (in the case of D=NO₂). The compound is useful for treatment of Alzheimer's disease, Parkinson's disease, brain functional disturbance, depression, schizophrenia, mania, an alcoholic disease, migraine, a sleep disturbance, cerabral ischemia and a stroke. Further, it is useful for treating T-lymphocyte propagation disturbance, asthma, incontinence of urine, arrhythmia, angina, diabetes mellitus or the like.

COPYRIGHT: (C)1996,JPO

Description

Detailed Description of the Invention

The present invention relates to a novel use of 6-amino-5-nitro- and -5-cyano-1,4-dihydropyridines, new 6-acylamino-dihydropyridines,
It relates to a method for their production, and in particular to their use as drugs as selective potassium channel modulators for treating the central nervous system.

The amino-substituted 1,4-dihydropyridines and their calcium antagonism are already known [in this connection, Arch. Pharm. 324
(2), 73-7, 1991; Arch. Pharm.
322 (5), 285-90, 1989 and DOS
22 10 674].

Surprisingly, the general formula (I)

[0004]

[Chemical 7]

[Wherein A represents aryl or pyridyl having 6 to 10 carbon atoms, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl. Alternatively, in each case it may be substituted up to 3 times with a straight-chain or branched alkylthio or alkoxy having up to 6 carbon atoms, D represents cyano or nitro, R
¹ represents hydrogen or represents a straight-chain or branched alkyl having up to 8 carbon atoms, R ² and R ³ are the same or different and represent hydrogen, or in each case 6 Represents a straight chain or branched alkyl or acyl having the following carbon atoms, R ⁴ represents hydrogen, or R ³ and R
⁴ together represent a group represented by the formula — (CH ₂ ) _n ,
Here, n represents the number 2, 3 or 4] 6
-Amino-5-nitro- and -5-cyano-1,4-
Dihydropyridines (some of which are known)
And their physiologically acceptable salts have selective regulatory effects on potassium channels and are suitable for use in combating cerebral and central nervous system (CNS) disorders, and sickle cell anemia. I found something.

Physiologically acceptable salts are generally the salts of the compounds according to the invention with inorganic or organic acids. Suitable salts are inorganic acids such as hydrochloric acid, hydrobromic acid,
Salts with phosphoric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid,
It is a salt with malic acid, citric acid, tartaric acid, lactic acid or benzoic acid, or with methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

The compounds according to the invention may exist in stereoisomeric forms, whether they behave as mirror images (enantiomers) or not as mirror images (diastereomers). The present invention relates to both antipodes and racemic forms, as well as diastereomeric mixtures. This racemic form, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

A represents phenyl, naphthyl or pyridyl, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl or in each case up to 4 carbon atoms. Optionally substituted with linear or branched alkylthio or alkoxy up to 3 times, D represents cyano or nitro, R ¹ represents a linear or branched alkyl having 6 or less carbon atoms, R ^{1 2} and R ³ are the same or different and represent hydrogen, or in each case represent a straight-chain or branched alkyl or acyl having up to 4 carbon atoms, R ⁴ represents hydrogen or R ³ and R ⁴ together form the formula - (CH ₂₎ a group represented by _n, where, n represents the number 2, 3 or 4, the compounds represented by the general formula (I) and It is preferable to use these salts.

To combat cerebral disease, A represents phenyl or pyridyl, each of which is optionally substituted in the same or different manner with nitro, cyano, phenyl, fluorine, chlorine, trifluoromethyl, methoxy or methylthio. It may be substituted up to a number of times, D represents cyano or nitro, R ¹ represents a straight chain or branched alkyl having 4 or less carbon atoms, R ² and R ³ are the same or different and are hydrogen. Or represents in each case a straight-chain or branched alkyl or acyl having up to 4 carbon atoms, R ⁴ represents hydrogen or R ³ and R ⁴ together are of the formula Represents a group represented by (CH ₂ ) _n , where:
It is particularly preferable to use the compounds represented by the general formula (I) and their salts, in which n represents the number 2 or 3.

The compounds of the general formula (I) according to the invention exhibit an unforeseeable and valuable pharmacological action spectrum.

These are channel regulators with surprising selectivity for large conductivities for calcium-dependent potassium channels (BK (Ca) channels), especially central nervous system potassium channels. They are simultaneously distinguished by not showing significant calcium channel activity.

On the basis of their pharmacological properties, they are associated with diseases which show substantial degeneration, for example diseases associated with the development of dementia (multiinfarction dementia).
dementia (MID), primary degenerative dementia (pri
Mary unique dementi
a) (PDD), elderly and senile Alzheimer's disease,
It can be used in the manufacture of a medicament suitable for the treatment of HIV dementia and other forms of dementia), Parkinson's disease or amyotrophic lateral sclerosis, as well as multiple sclerosis.

The active compounds are furthermore suitable for treating age-related cerebral dysfunction, organic brain syndrome (OBS) and age-related memory impairment (AAMI).

They are suitable for the prevention and treatment of diseases which occur as a result of cerebral circulatory disorders, such as cerebral ischemia, stroke, cranial trauma and subarachnoid hemorrhage and to combat these diseases.

They are of value in the treatment of depression and psychosis, such as schizophrenia. They are furthermore suitable for the treatment of neuroendocrine and neurotransmitter secretion disorders and related health disorders such as mania, alcoholism, substance abuse, addiction or pathological dietary behavior. Another field of use is in the treatment of migraine, sleep disorders and neuropathy. They are also suitable as analgesics.

The active compounds are further used for the treatment of immune system disorders,
Particularly suitable for the treatment of T lymphoproliferative disorders, as well as for affecting the smooth muscle system, in particular the uterus, bladder and bronchial tracts, and the related diseases such as asthma and urinary incontinence. And suitable for use in the treatment of arrhythmias, angina and diabetes.

The present invention further includes the general formula (I)

[0018]

Embedded image

It also relates to novel compounds of the formula and their salts, in which the meanings of these substituents are given in the table below:

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

The compounds according to the invention and the novel substances of the general formula (I) have the general formula (II)

[0027]

[Chemical 9]

[0028] [wherein, A and R ¹ has the abovementioned meaning, R ¹ does not represent hydrogen, a compound represented by the case of D = NO _2, the general formula (III)

[0029]

[Chemical 10]

By reacting with a compound of the formula where R ² and R ³ have the meanings given above, and in the case of D = CN, optionally in the presence of an ammonium salt, preferably ammonium acetate, in an organic solvent Of the general formula (IV) (R ² / R ³ = H)

[0031]

[Chemical 11]

[In the formula, Z represents C ₁ -C ₄ -alkyl]
When R ² and / or R ³ ≠ H, the product is reacted with a corresponding alcoholic amine solution, or when appropriate alkylation or acylation is carried out, It can be prepared using methods in which they are reacted in an organic solvent in the presence of a base, and when R ¹ = H, hydrolysis of the ester occurs in the usual manner.

The method according to the invention can be described by way of example with the following equation:

[0034]

[Chemical 12]

Suitable solvents here are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, acetonitrile,
Or amides, such as hexamethylphosphoric triamide, or dimethylformamide, or acetic acid or halogenated hydrocarbons, such as methylene chloride or carbon tetrachloride, or hydrocarbons, such as benzene or toluene. It is also possible to use mixtures of the solvents mentioned. Isopropanol, ethanol, tetrahydrofuran, methanol, dioxane and dimethylformamide are particularly suitable.

Suitable bases are generally alkali metal hydrides or alcoholates, such as sodium or potassium tert-butylate hydride, or cyclic amines, such as piperidine or dimethylaminopyridine, or C ₁ -C. ₄ -alkylamines such as triethylamine. Piperidine, dimethylaminopyridine, pyridine, sodium hydride and potassium tert-butylate are preferred.

The substances participating in this reaction can be used in any proportion desired in the practice of the process according to the invention. However, generally these reactants are used in equimolar amounts.

The reaction temperature can be changed within a relatively wide range. In general, the reaction is carried out at + 10 ° C. to + 150 ° C., preferably + 20 ° C. to + 100 ° C., especially at the boiling point of the individual solvent.

The reaction can be carried out under normal pressure, elevated pressure or reduced pressure (for example 0.5 to 3 bar). Generally, this reaction is carried out under normal pressure.

Suitable solvents for the alkylation are likewise customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether,
Dioxane, tetrahydrofuran or glycol dimethyl ether and the like, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethylene,
Examples include trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

Suitable bases are generally alkali metal hydrides or alcoholates, such as sodium or potassium tert-butylate hydride, or cyclic amines, such as piperidine or dimethylaminopyridine, or C ₁ -C. ₄ -alkylamines such as triethylamine. Sodium hydride is preferred.
The reaction temperature can be changed within a relatively wide range. Generally, + 10 ° C to + 150 ° C, preferably +20
The reaction is carried out at from 0 ° C to + 100 ° C, especially at room temperature.

0 ° C to + 150 ° C, preferably room temperature to +
Alkylation is carried out in the above solvent at a temperature of 100 ° C.

The reaction can be carried out under normal pressure, elevated pressure or reduced pressure (for example 0.5 to 3 bar). Generally, this reaction is carried out under normal pressure.

The compound 1 to be alkylated in each case
The base is generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol per mol.

Suitable bases for use in the acylation are organic bases such as organic tertiary amines, trialkyl (C _1-
C ₆₎ amines, such as triethylamine, etc., or heterocyclic compounds, such as pyridine, and the like 4- (N, N- dimethylamino) pyridine or methylpiperidine. Triethylamine is particularly preferred.

Suitable solvents for the acylation are likewise customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum cuts, or halogenated hydrocarbons, Examples include methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is possible to use mixtures of the solvents mentioned, or else to use the individual acylating agents as solvents. Acetic anhydride and piperidine are preferred.

This acylation is generally carried out under atmospheric pressure from 0 ° C. to +1.
Proceed at a temperature in the range of 20 ° C, preferably + 30 ° C to + 90 ° C.

Hydrolysis of the carboxylic acid ester is carried out in the usual way by treating the ester with a conventional base in an inert solvent.

Suitable bases for use in this hydrolysis are the usual inorganic bases. These are preferably alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or carbonate. Includes potassium and the like, or sodium bicarbonate and the like. Sodium hydroxide or potassium hydroxide is particularly preferably used. Suitable solvents for this hydrolysis are water or the organic solvents customary for hydrolysis. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

Generally, 0 ° C to + 100 ° C, preferably +
The hydrolysis is carried out at temperatures ranging from 20 ° C to + 80 ° C.

The hydrolysis is generally carried out under normal pressure.
However, it is also possible to carry out the hydrolysis under reduced pressure or under increased pressure (for example 0.5 to 5 bar).

For example, separation of a diastereomeric mixture of compounds of the general formula (I) may be carried out in the usual way, followed by direct transesterification of the diastereomers, or else of the chiral carboxylic acid first. After preparation, the procedure by preparing the enantiomerically pure dihydropyridines by esterification is used to provide the enantiomerically pure form.

Separation of diastereomers is generally carried out by fractional crystallization, column chromatography, or Craig partition. The optimum method should be determined individually, and it is sometimes convenient to use a combination of individual methods. It is particularly suitable to carry out crystallization or Craig partition or a combination of the two methods for the separation.

The enantiomerically pure compounds can also be obtained by subjecting the racemic esters to chromatography using a chiral phase.

General formulas (II), (III) and (I
The compound represented by V) is known or can be produced by a conventional method.

The compounds of the general formula (I) according to the invention have an unforeseeable and valuable action, especially on the basis of their selectivity for large conductivities for calcium-dependent potassium channels. The spectrum is shown.

⁸⁶ ruby from C6-BU1 glioma cells
The method described by Tas et al. (Neurosci. Let.
t. 94, 279-284 (1988)) with a slight modification. In this experiment, rat C
A 6-BU1 glioma cell culture was used. The increase in ⁸⁶ rubidium outflow over the basal outflow caused by ionomycin was calculated from the data and calculated as 100
Set to%. Therefore, the stimulation in the presence of the test substance is based on this value.

The present invention also relates to a pharmaceutical preparation or formula containing one or more compounds of the general formula (I) in addition to inert, non-toxic pharmaceutically suitable auxiliaries and excipients. It also relates to pharmaceutical preparations which consist of one or more active compounds of the formula (I), as well as the process for the preparation of these preparations.

The active compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, based on the total mixture. is there. In addition to the active compound of formula (I), the pharmaceutical preparations may also contain other compounds which exhibit a pharmacological activity.

The abovementioned pharmaceutical preparations can be manufactured in a customary manner by known methods, for example using the auxiliaries or excipient substances or substances.

To achieve the desired results, in general, 1 kg of body weight every 24 hours in the form of individual doses divided into a number of suitable doses.
It has been found to be advantageous to administer the active compound or compounds of formula (I) in a total amount of about 0.01 to about 100 mg, preferably in a total amount of about 1 mg to 50 mg per did.

However, it is also advantageous, if appropriate, to deviate from the amounts mentioned above, in particular this deviation being due to the nature and weight of the subject to be treated, the individual behavior towards the drug, the nature and severity of the illness, the nature of the preparation and administration. , And as a function of time and interval between administrations.

[0063]

EXAMPLES Starting compounds Example I Methyl 2-acetyl-3- (3-chloro-4-trifluoromethylphenyl) acrylate

[0064]

[Chemical 13]

3-Chloro-4-trifluoromethylbenzaldehyde in 32 mL of 200 mL methylene chloride.
3 g (155 mmol) and 1 of methyl acetoacetate
After dissolving 8.0 g (155 mmol), 1.2 mL piperidine and 1 mL glacial acetic acid are added. The mixture is heated with a water separator for 5 hours. It is then washed with water, dried over MgSO ₄ and then concentrated. The product is recrystallized twice with methanol. This gives 25.6 g (54% of theory) of the title compound.

Example II 1-N-methylamino-2-nitro-ethylene-1-amine

[0067]

Embedded image

25.0 g of 1,2-bis (methylthio) -2-nitroethane in 300 mL of ethanol
After dissolving (0.15 mol), methylamine hydrochloride was added to 1
Add 1.9 g (0.18 mol). After heating the mixture to reflux temperature, a total of 20.2 g (0.18 mol) of potassium tert-butylate is added in 4 portions every 30 minutes. The mixture is then kept under reflux for 1 hour (thin layer chromatography control: ethyl acetoacetate / petroleum ether 3: 1). It was concentrated, the residue was taken up in methylene chloride, the mixture was washed with water and then dried over sodium sulphate. Then it is concentrated and the residue is filtered over silica gel (methylene chloride). The product is crystallized from ethanol. The isolated solid is then dissolved in 200 mL of butanol and ammonia is passed through this solution for 2 hours under reflux (thin layer chromatography control). After distilling off the solvent, the residue is crystallized from ethanol.

Yield: 2.9 g (16% of theory) Preparation Examples Example 1 6-Amino-4- (3-chloro-4-trifluoromethylphenyl) -1,4-dihydro-2-methyl- 5-Nitro-3-carboxylic acid methyl ester

[0070]

[Chemical 15]

After dissolving 15.3 g (50 mmol) of the compound obtained in Example I and 5.2 g (50 mmol) of 2-nitro-1,1-ethenediamine in 80 mL of ethanol, the solution was refluxed. Hold down for 12 hours. After cooling, the solid formed is filtered off with suction and washed with ethanol. 13.0 g of the title compound (66 theoretical)
%)can get.

Melting point: 250 ° C. The compounds shown in Table 1 are prepared according to the teaching of Example 1.

[0073]

[Table 7]

Example 5 Methyl 6-acetylamino-4- (3-chloro-4-trifluoromethylphenyl) -1,4-dihydro-2-methyl-3-nitro-5-carboxylate

[0075]

Embedded image

After dissolving 4.0 g (10.2 mmol) of the compound obtained in Example 1 in 40 mL of acetic anhydride,
The mixture is heated under reflux for 12 hours. Next, acetic anhydride was distilled under reduced pressure, was dissolved the residue in methylene chloride, the mixture is washed with saturated aqueous NaHCO _3. The organic phase is dried (MgSO ₄ ) and concentrated, then the residue is purified by chromatography on silica gel (toluene / AcOEt / iPrOH 10).
0 + 10 + 1). The eluent is concentrated and recrystallized from ethanol. 0.5 g of the title compound (1 theoretical)
1%) is obtained. Melting point: 152 ° C. The compounds shown in Table 2 are prepared as in Example 5.

[0077]

[Table 8]

Example 14 4- (2,3-Dichlorophenyl) -3-methoxycarbonyl-2-methyl-3-nitro-1,7-diaza [4.3.0] bicyclonona-2,4-diene

[0079]

[Chemical 17]

2-Acetyl-3 in 30 mL of ethanol
5.7 g (20 mmol) of (2,3-dichlorophenyl) acrylic acid methyl ester and 2.6 g (20 mmol) of 2-nitromethylene-1,3-diazolidine.
After dissolution, the solution is heated at 80 ° C for 18 hours.
After cooling, the solid formed is filtered off with suction and washed with ethanol. Next, this is suspended in toluene, 20 mg of p-toluenesulfonic acid is added, and this mixture is kept under reflux for 18 hours using a water separator. The solid which precipitates on cooling is filtered off with suction. The title compound is 6.
1 g (79% of theory) are obtained.

Melting point: 225 ° C. The compounds shown in Table 3 are prepared in analogy to the teaching of Example 14.

[0082]

[Table 9]

Example 22 1,4-Dihydro-2-methyl-6-methylamino-4
-(3-chloro-4-trifluoromethylphenyl)-
5-Nitro-3-carboxylic acid methyl ester

[0084]

Embedded image

2.9 g of 1-N-methylamino-2-nitroethylene-1-amine was added to 100 mL of ethanol.
After dissolving 6.7 g (25 mmol) of (25 mmol) and methyl 2-acetyl-3- (3-chloro-4-trifluoromethylphenyl) acrylate, the solution is heated under reflux overnight. After concentrating the reaction mixture, the residue is chromatographed twice on silica gel (1: methylene chloride: AcOEt (gradient),
2: Methylene chloride: MeOH 100 + 1). EtOH
After recrystallization from / acetonitrile, 1.2 g (21.6% of theory) of the title compound are obtained.

The compounds shown in Table 4 are prepared in analogy to the teaching of Example 22.

[0087]

[Table 10]

Example 25 Methyl 6-amino-5-cyano-2-methyl-4- (4-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate

[0089]

[Chemical 19]

13.6 g in 100 mL of methanol
(50 mmol) methyl 2-acetyl-3- (4-trifluoromethylphenyl) acrylate and 7.45 g
(50 mmol) Hydrochloric acid cyanoacetimidic acid ethyl ester and 15 g (190 mmol) ammonium acetate are heated under reflux for 1 hour. After concentrating the mixture, the residue is partitioned between ice water and ethyl acetate. The organic phase is washed twice with dilute aqueous NaHCO ₃ solution and once with water, dried over Na ₂ CO ₃ and then concentrated in vacuo. The residue (18.4 g) is crystallized from methanol to give 6.3 g (37% of theory) of colorless crystals of the title compound.

Melting point: 210-214 ° C. The compounds shown in Table 5 are prepared in analogy to the teaching of Example 25.

[0092]

[Table 11]

Example 29 Methyl 6-acetamido-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylate

[0094]

Embedded image

6.7 g (20 mmol) of 6-amino-
5-cyano-4- (2,3-dichlorophenyl) -2-
Methyl methyl-1,4-dihydropyridine-3-carboxylate and 33.5 mL (350 mmol) acetic anhydride are heated under reflux for 30 minutes. The excess acetic anhydride is then converted to methyl acetate by adding methanol with stirring at 25 ° C. The reaction solution was evaporated in vacuum and the toluene desolvent from the residue was removed in vacuo.
Do it once. Then the residue is boiled with 50 mL of toluene. The separated crystals are filtered off and washed with toluene.

Yield: 3.6 g (50% of theory) Melting point: 224 ° C. (decomposition) The compounds shown in Table 6 are prepared in analogy to the teaching of Example 29.

[0097]

[Table 12]

Example 36 5-Cyano-4- (2,3-dichlorophenyl) -2-
Methyl-6-methylamino-1,4-dihydropyridine-3-carboxylic acid methyl ester

[0099]

[Chemical 21]

2.8 g (10 mmol) of methyl 2-acetyl-3- (2,3-dichlorophenyl) acrylate and 1.5 g (10 mmol) of ethyl cyanoacetimic acid hydrochloride were added to an ethanol solution of methylamine (33).
% Concentration) is added in 5 mL (40 mmol). The mixture is warmed to 46 ° C. After cooling to 30 ° C, 2.3 mL
(40 mmol) glacial acetic acid is added followed by 20 mL methanol. After heating under reflux for 5 hours, ice water is added to the reaction solution and the mixture is extracted with ethyl acetoacetate. After drying the organic phase (Na ₂ SO ₄ ),
Concentration under reduced pressure gave 3.9 g of amorphous residue.
Obtained and chromatographed on 100 g of silica gel, using toluene / ethyl acetoacetate (gradient) here.

Yield: 0.5 g (10% of theory) of crystals Melting point: 234-239 ° C. The compounds shown in Table 7 are prepared in analogy to the teaching of Example 36.

[0102]

[Table 13]

The features and aspects of the present invention are as follows.

1. General formula (I) for the manufacture of a medicament having a selective regulatory action on potassium channels, which is suitable for treating the central nervous system

[0105]

[Chemical formula 22]

[Wherein A represents aryl or pyridyl having 6 to 10 carbon atoms, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl. Alternatively, in each case it may be substituted up to 3 times with a straight-chain or branched alkylthio or alkoxy having up to 6 carbon atoms, D represents cyano or nitro, R
¹ represents hydrogen or represents a straight-chain or branched alkyl having up to 8 carbon atoms, R ² and R ³ are the same or different and represent hydrogen, or in each case 6 Represents a straight chain or branched alkyl or acyl having the following carbon atoms, R ⁴ represents hydrogen, or R ³ and R
⁴ together represent a group represented by the formula — (CH ₂ ) _n ,
Here, n represents the number 2, 3 or 4] 6
-Use of amino-dihydropyridines and their physiologically acceptable salts.

2. General formula (I) for the manufacture of a medicament having a selective regulatory action on potassium channels, which is suitable for treating the central nervous system

[0108]

[Chemical formula 23]

[Wherein A represents aryl or pyridyl having 6 to 10 carbon atoms, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl. Alternatively, in each case it may be substituted up to 3 times with a straight-chain or branched alkylthio or alkoxy having up to 6 carbon atoms, D represents cyano or nitro, R
¹ represents hydrogen or represents a straight-chain or branched alkyl having up to 8 carbon atoms, R ² and R ³ are the same or different and represent hydrogen, or in each case 6 Represents a straight-chain or branched alkyl or acyl having the following carbon atoms, wherein at least one of these substituents represents an acyl group and R ⁴ represents hydrogen or R ³ and R ⁴ There together formula - represents a group represented by (CH _{2) n,} where, n is a novel 6-acylamino represented by] represents the number 2, 3 or 4 - dihydropyridines and their Physiologically acceptable salts.

3. A novel compound represented by the general formula (I) according to item 1 selected from the group of 40 embodiments.

4. In the method for producing the compound represented by the general formula (I) described in the first item, the compound represented by the general formula (II)

[0112]

[Chemical formula 24]

[0113] [wherein, A and R ¹ has the abovementioned meaning, R ¹ does not represent hydrogen, a compound represented by the case of D = NO _2, the general formula (III)

[0114]

[Chemical 25]

Reacting with a compound of the formula: wherein R ² and R ³ have the meanings given above, and D = CN
In the presence of an ammonium salt, preferably ammonium acetate, in the organic solvent of formula (IV) (R ² / R ³ = H)

[0116]

[Chemical formula 26]

[In the formula, Z represents C ₁ -C ₄ -alkyl]
When R ² and / or R ³ ≠ H, the product is reacted with a corresponding alcoholic amine solution, or when appropriate alkylation or acylation is carried out, A process characterized in that they are reacted in an organic solvent in the presence of a base and, if R ¹ = H, the hydrolysis of the ester takes place in the usual way.

5. General formula (I)

[0119]

[Chemical 27]

[Wherein A represents phenyl or pyridyl, each optionally substituted in the same or different manner with nitro, cyano, phenyl, fluorine, chlorine, trifluoromethyl, methoxy or methylthio no more than twice. Optionally, D represents cyano or nitro,
R ¹ represents a straight-chain or branched alkyl having up to 4 carbon atoms, R ² and R ³ are the same or different and represent hydrogen, or in each case have up to 4 carbon atoms Represents straight-chain or branched alkyl or acyl, wherein at least one of these substituents represents acyl, R ⁴ represents hydrogen, or R ³ and R ⁴ together are ethylene or Representing a propylene group] and salts thereof.

6. An agent for selectively treating potassium channels in the central nervous system, which comprises at least one compound represented by the general formula (I) according to item 1.

7. A method for producing a drug, which comprises converting at least one compound represented by the general formula (I) described in item 1 into a suitable dosage form together with a usual auxiliary agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07D 471/04 108 A // C07D 211/90 (72) Inventor Hans-Georg Heine Germany 47800 Clay Felt Amhecker Ruhoff 14 (72) Inventor Bod Junge Germany 42399 Buttpertal Syupiekerun 46 (72) Inventor Rudolf Schijoe Rope Germany 42327 Butzpertal Arundt Siuttrase 10 Ar (72) Inventor Henning Sommermayer Germany 51061 Cologne Salvator Schutlerse 25 (72) Inventor Thomas Glazer Germany 51491 Off Errat Biedenhoff 8 (72) Inventor Rilinde Bittuka Germany 51069 Cologne Heideschutlerse 21 (72) Inventor J Jan-Marie-Victor de Bry Germany 51503 Leslat Adelenhof 36

Claims (5)

[Claims] 1. A compound of general formula (I): embedded image for producing a drug having a selective regulatory action on potassium channels, which is suitable for treating the central nervous system. Wherein A represents aryl or pyridyl having 6 to 10 carbon atoms, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl or In any case it may be substituted three or less times with a straight or branched alkylthio or alkoxy having 6 or less carbon atoms,
D represents cyano or nitro, R ¹ represents hydrogen or linear or branched alkyl having 8 or less carbon atoms, R ² and R ³ are the same or different and each represent hydrogen. Represents, or in each case represents a straight-chain or branched alkyl or acyl having up to 6 carbon atoms, R ⁴ represents hydrogen or R ³ and R ⁴ together are of the formula Represents a group represented by (CH ₂ ) _n , where n is
Representing the number 2, 3 or 4] and the use of 6-amino-dihydropyridines and physiologically acceptable salts thereof. 2. A compound of the general formula (I): for preparing a drug having a selective regulatory action on potassium channels, which is suitable for treating the central nervous system. Wherein A represents aryl or pyridyl having 6 to 10 carbon atoms, each of which is optionally in the same or different manner nitro, cyano, phenyl, halogen or trifluoromethyl or In any case it may be substituted three or less times with a straight or branched alkylthio or alkoxy having 6 or less carbon atoms,
D represents cyano or nitro, R ¹ represents hydrogen or linear or branched alkyl having 8 or less carbon atoms, R ² and R ³ are the same or different and each represent hydrogen. Represents, or in each case represents a straight-chain or branched alkyl or acyl having up to 6 carbon atoms, wherein at least one of these substituents represents an acyl group and R ⁴ represents hydrogen. Or R ³ and R ⁴ together represent a group of the formula — (CH ₂ ) _n , where n represents the number 2, 3 or 4] 6-acylamino-dihydropyridines and their physiologically acceptable salts. 3. A method for producing a compound represented by the general formula (I) according to claim 1, wherein the compound represented by the general formula (II): Wherein A and R ¹ have the meanings given above, but R ¹
Does not represent hydrogen], and in the case of D = NO ₂ , a compound represented by the general formula (III): Where R ² and R ³ have the meanings given above, and when D = CN, optionally in the presence of an ammonium salt, preferably ammonium acetate,
The compound of the general formula (IV) (R ² / R ³ = H) in an organic solvent Reacting with a compound of the formula Z represents C ₁ -C ₄ -alkyl and, in the case of R ² and / or R ³ ≠ H, reacting the product with the corresponding alcoholic amine solution. Or if appropriate alkylation or acylation is carried out, they are reacted in the presence of a base in an organic solvent and, if R ¹ = H, hydrolysis of the ester occurs in the usual way. A method characterized by the following. 4. A compound represented by the general formula (I): Wherein A represents phenyl or pyridyl, each of which is optionally in the same or different manner nitro, cyano, phenyl, fluorine, chlorine, trifluoromethyl,
It may be substituted no more than twice with methoxy or methylthio, D represents cyano or nitro, R ¹ represents a straight-chain or branched alkyl having 4 or less carbon atoms, R ² and R ³ are , Identical or different, each representing hydrogen, or in each case representing a straight-chain or branched alkyl or acyl having up to 4 carbon atoms, wherein:
At least one of these substituents represents acyl and R ⁴
Represents hydrogen, or R ³ and R ⁴ together represent an ethylene or propylene group] and salts thereof. 5. An agent for selectively treating potassium channels in the central nervous system, which comprises at least one compound represented by the general formula (I) according to claim 1.